PENETRATION ENHANCERS final

Guided By: Presented By: Asst. Prof. Ramakant Patil Mrs. S. A. Aphale M. Pharm(2nd Sem) (Roll No. : 212) SINHGAD INSTITUTE OF PHARMACY NARHE, PUNE-41 :

Guided By: Presented By: Asst. Prof. Ramakant Patil Mrs. S. A. Aphale M. Pharm (2 nd Sem ) ( Roll No. : 212) SINHGAD INSTITUTE OF PHARMACY NARHE, PUNE-41 Penetration Enhancers 5/7/2011 1 PENETRATION ENHANCERS

CONTENT:

CONTENT Objectives of study Introduction Structure of skin Barrier properties Percutaneous absorption Factors affecting percutaneous absorption Penetration enhancement Classification of CPE’s General comments Physical enhancement techniques 5/7/2011 2 PENETRATION ENHANCERS

OBJECTIVES:

OBJECTIVES To understand the skin structure & its barrier function. To study factor affecting penetration through skin. To study various approaches to enhance drug penetration through skin, including 1. Type 2. Need 3. Mode of action. 5/7/2011 3 PENETRATION ENHANCERS

INTRODUCTION:

INTRODUCTION The aim of drug administration via skin can be either the local therapy or the transdermal drug delivery of the systemic circulation. Transdermal system delivers medications through the skin direct into the blood stream. One long standing approach to increase the range of drugs that can effectively delivered via this route has been to use penetration enhancers: chemicals that interact with skin constituents to promote drug flux. 5/7/2011 4 PENETRATION ENHANCERS

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A diagrammatical cross-section through human skin 5/7/2011 5 PENETRATION ENHANCERS

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Weight of skin: 8 pounds Surface Area: 20,000 sq. cm. Three layers: Epidermis (Stratum corneum ):dead keratinized cells, density 1.55, palms& soles : 100 micrometer. Other portions: 10 micrometer in dry state & 40 to 50 micrometer in hydrated state. Dermis: consists of proteins in a matrix of muco polysaccharide, blood vessels,lymphatics,nerves,hair follicles, sebaceous & sweat glands. Subcutaneous layer 5/7/2011 6 PENETRATION ENHANCERS

BARRIER PROPERTIES OF SKIN :

BARRIER PROPERTIES OF SKIN 5/7/2011 7 PENETRATION ENHANCERS

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PERCUTANEOUS ABSORPTION:

PERCUTANEOUS ABSORPTION It involves passive diffusion of substance through skin. Transcorneal penetration: Intra cellular penetration. Inter cellular penetration. Transappendegeal Penetration. 5/7/2011 9 PENETRATION ENHANCERS

FACTORS AFFECTING PERCUTANEOUS ABSORPTION:

FACTORS AFFECTING PERCUTANEOUS ABSORPTION Solubility in stratum corneum Diffusion through stratum corneum Partitioning Diffusion through viable skin tissue Condition of skin Effect of moisture Effect of vehicles Effect of concentration of medicament Effect of surfactant 5/7/2011 10 PENETRATION ENHANCERS

PENETRATION ENHANCEMENT:

PENETRATION ENHANCEMENT Skin penetration enhancement technique have been developed to improve bioavailability & increase the range of drugs for which topical & transdermal delivery. Penetration enhancers penetrates through skin to decrease the barrier resistance. Alternatively, physical mechanism such as iontophoresis & phonophoresis can be used for certain cases of drugs. 5/7/2011 11 PENETRATION ENHANCERS

CHEMICAL ENHANCERS:

CHEMICAL ENHANCERS Chemical enhancers or penetration enhancers or absorption promoters are the agents that interact with skin constituents to promote the drug flux. Many agent have studied & evaluated for enhancement properties. Yet their inclusion in skin formulation is limited due to unknown mechanism & toxicity. 5/7/2011 12 PENETRATION ENHANCERS

IDEAL PROPERTIES:

IDEAL PROPERTIES Non toxic, non irritating, non allergic. Ideally work rapidly. Pharmacologically inert. Its duration of action should be predictable & reproducible. Should work unidirectionally. When removed from skin barrier properties should return both rapidly & fully. Cosmetically acceptable. Compatible with both excipients & drug. 5/7/2011 13 PENETRATION ENHANCERS

DIFFUSION THROUGH SKIN:

DIFFUSION THROUGH SKIN Fick’s 2 nd Law of diffusion dC / dt = D d 2 C/dx 2 ---------- (1) Where, C = Conc. Of drug x = space co-ordinate D = Diffusion coefficient t = Time Under steady state condition, dm / dt = D C 0 / h ----------------(2) Where, m= cumulative mass of drug that passes per unit area of membrane in time t C 0 = Conc. of diffusant in the first layer of membrane at the skin surface h = Membrane thickness 5/7/2011 14 PENETRATION ENHANCERS

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C 0 = P C’ 0 ---------- (3) where, P = Partition coefficient Substituting eq. (3) in eq. (2) gives dm / dt = D C’ 0 P / h ----------- (4) From equation it can be seen that : 1. Diffusion coefficient of drug in stratum corneum. 2. Dissolved effective conc. of drug in the vehicle. 3.Partition coefficient of drug between the formulation & stratum corneum. 4. Membrane thickness. 5/7/2011 15 PENETRATION ENHANCERS

EFFECTIVE PENETRATION ENHANCER MAY ACT :

EFFECTIVE PENETRATION ENHANCER MAY ACT By increasing the diffusion coefficient of the drug. By increasing the effective concentration of the drug in the vehicle. By improving partitioning between the formulation and the stratum corneum. By decreasing the skin thickness. 5/7/2011 16 PENETRATION ENHANCERS

CLASSIFICATION OF CPE’s:

CLASSIFICATION OF CPE’s 1. Surfactants : a) Ionic: SLS, Na laureate, etc. b) Non ionic : Tween 80, Polysorbates, etc. 2. Bile Salts & Derivatives : E.g.. Na glyacolate, Na deoxycholate 3. Fatty Acid & Derivatives : E.g.. Oleic acid, Caprylic acid, etc. 4. Chelating Agents : E.g.. EDTA, Citric acid, etc. 5/7/2011 17 PENETRATION ENHANCERS

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5. Sulphoxide : E.g.. DMSO, DMA, DMF, etc. 6. Polyols : E.g. : PG, PEG, Glycerol, etc. 7. Monohydric Alcohols : E.g. : Ethanol, 2- Propanol, etc. 8. Miscellaneous : E.g. : a) Urea & its derivatives b) Terpenes & Terpenoids c) Phospholipids d) Water 5/7/2011 18 PENETRATION ENHANCERS

MODE OF ACTION:

MODE OF ACTION 5/7/2011 19 PENETRATION ENHANCERS

WATER:

WATER The water content of human stratum corneum is typically around 15-20% of tissue dry weight. Soaking the skin in water, exposing the membrane to high humidities or, occluding allow the stratum corneum to reach water contents in equilibrium with underlying epidermal skin cells. Water content increases to 400% In general, increased tissue hydration appears to increase transdermal delivery of both hydrophilic & lipophilic permeants 5/7/2011 20 PENETRATION ENHANCERS

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Water present in stratum corneum is in two form, bound & free, Free form act as solvent for polar permeants to diffuse. MOA: - free water act as solvent & alter solubility of permeants & so its partitioning. . - The corneocytes take up water and swell, such swelling of cells would impact upon the lipid structure between the corneocytes causing some disruption to the bilayer packing. 5/7/2011 21 PENETRATION ENHANCERS

SULPHOXIDE & ITS ANALOUGE:

SULPHOXIDE & ITS ANALOUGE Dimethyl sulphoxide(DMSO), aprotic solvent which form hydrogen bond with itself rather than with water. used in many areas of pharmaceutical sciences as a ‘‘universal solvent’’. Promotes both hydrophilic & hydrophobic permeants. Effect is concentration dependent(> 60% needed for optimum action). At high concentration – erythema & whales, may denature proteins. Metabolite dimethyl sulfide produces foul odor on breath. 5/7/2011 22 PENETRATION ENHANCERS

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To avoid above side effects researchers have investigated chemically related materials – DMAC & DMF MOA: - denature protein, changes the keratin confirmation from α - helical to β – sheet. - interacts with the head groups of some bilayer lipids to distort to the packing geometry. - also may facilitate drug partitioning from formulation to this universal solvent. 5/7/2011 23 PENETRATION ENHANCERS

AZONES:

AZONES First chemically design molecule as penetration enhancer. Promote flux both hydrophilic & lipophilic permeants. Highly lipophilic with Log o/w =6.2. Effective at low concentration(0.1 – 5%). Soluble in & compatible with most organic solvents. Enhances permeation of steroids, antiviral & antibiotics. MOA: - Interact with the lipid domains of the stratum corneum. - Partition into the lipid bilayer to disrupt their packing arrangement. 5/7/2011 24 PENETRATION ENHANCERS

PYRROLIDONES:

PYRROLIDONES Mostly used member : 2- Pyrrolidone(2P) & N- Methyl -2- Pyrrolidone(NMP). NMP & 2P are miscible with most organic solvents. Used for numerous molecules including hydrophilic (e.g. mannitol, & 5-FU) and lipophilic ( hydrocortisone and progesterone) permeants. Greater effect on hydrophilic drugs. MOA: - may act by altering the solvent nature of the membrane and pyrrolidones have been used to generate ‘reservoirs’ within skin membranes. - Such a reservoir effect offers potential for sustained release of a permeant. 5/7/2011 25 PENETRATION ENHANCERS

FATTY ACIDS:

FATTY ACIDS Oleic acid & other long chain fatty acid are used. Effective at low concentration(<10%) Used both for hydrophilic & lipophilic drugs. Saturated alkyl chain lengths of around C10–C12 attached to a polar head group yields a potent enhancer. In unsaturated compounds, the bent cis configuration is expected to disturb intercellular lipid packing more than trans. Used for estradiol, acyclovir, 5 FU, Salicylic acid. MOA: - Interacts with & modifies the lipid domains of stratum corneum discrete lipid domains is induced within stratum corneum bilayer lipid on exposure to oleic acid. 5/7/2011 26 PENETRATION ENHANCERS

ALCOHOLS, FATTY ALCOHOLS & GLYCOLS:

ALCOHOLS, FATTY ALCOHOLS & GLYCOLS Ethanol is used most commonly in patches. Used for levonorgestrol, estrdiol, 5 FU, etc. Its effect is concentration dependent, at high concentration causes dehydration of biological membrane & decreases the permeation. Applied in concentration range from 1 – 10%. Branched alkanols lower activity 1- Butanol most effective. 1-octanol and 1-propranolol to be effective enhancers for salicylic acid and nicotinamide. 5/7/2011 27 PENETRATION ENHANCERS

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MOA: Act as solvent. alter solubility property of tissue leads to improvement in drug partitioning. volatile nature of ethanol help in modifying thermodynamic activity of drug. due to evaporation of ethanol drug concentration increases providing supersaturated state with greater driving force Solvent drag may carry permeant into the tissue. As volatile solvent may extract lipid fraction from skin. 5/7/2011 28 PENETRATION ENHANCERS

SURFACTANT:

SURFACTANT Are made up of alkyl or aryl side chain with polar head group. Have potential to damage human skin. Both anionic & cationic surfactant can be used, but non ionic surfactant are safe. Non ionic – minor effect, anionic – pronounced effect. MOA: - Solubalise the lipophilic active ingredient & also have potential to solubalise lipids within the stratum corneum. 5/7/2011 29 PENETRATION ENHANCERS

ESSENTIAL OILS, TERPENES & TERPENOIDS:

ESSENTIAL OILS, TERPENES & TERPENOIDS Used as medicines, flavoring and fragrance agents. Hydrocarbon terpenes less potent, alcohol/ ketone containing terpenes moderate and oxide & terpenoid shows greatest enhancement . Smaller terpenes are more active than larger. Non polar(limonene) agents active for lipophilic drugs & polar(menthol) for hydrophilic drugs. MOA: - Modify the solvent nature of the stratum corneum, improving drug partitioning. - Alters thermodynamic activity of the permeant. - Terpenes may also modify drug diffusivity through the membrane. 5/7/2011 30 PENETRATION ENHANCERS

UREA:

UREA Hydrating agent, have been used in scaling conditions such as psoriasis & other skin conditions. It produces significant stratum corneum hydration, produces hydrophilic diffusion channels. Has keratolytic properties, usually when used in combination with salicylic acid for keratolysis. Urea itself possesses only marginal penetration enhancing activity. Cyclic urea analogues and found them to be as potent as Azone for promoting indomethacin. 5/7/2011 31 PENETRATION ENHANCERS

PHOSPHOLIPIDS:

PHOSPHOLIPIDS Generally employed as vesicles (liposomes) to carry drugs. In a non-vesicular form as penetration enhancers. Phosphatidylcholine & hydrogenated soya bean phospholipids have been reported to enhance penetration of theophylline & diclofenac respectively. MOA: - occlude the skin surface & thus increase tissue hydration. - phospholipids fuse with stratum corneum lipids. - this collapse of structure liberates permeant into the vehicle where drug is poorly soluble and hence thermodynamic activity could be raised so facilitating drug delivery. 5/7/2011 32

GENERAL COMMENTS:

GENERAL COMMENTS It is difficult to select rationally a penetration enhancer for a given permeant. Penetration enhancers tend to work well with co-solvents such as PG or ethanol. Most penetration enhancers have a complex concentration dependent effect. Permeation through animal skins & rodent skins are generally considerably greater than those obtained with human skin. 5/7/2011 33 PENETRATION ENHANCERS

DIRECT EFFECTS:

DIRECT EFFECTS Act on the stratum corneum intracellular keratin, denature it or modify its conformation. Affect the desmosomes that maintain cohesion between corneocytes. Modify the intercellular lipid domains to reduce the barrier resistance of the bilayer lipids. Alter the solvent nature of the stratum corneum to modify partitioning of the drug. 5/7/2011 34 PENETRATION ENHANCERS

INDIRECT EFFECTS:

INDIRECT EFFECTS Modification of thermodynamic activity of the vehicle. Solvent permeating through the membrane could ‘drag’ the permeant with it. Solubalising the permeant in the donor, especially where solubility is very low so that can reduce depletion effects and prolong drug permeation. 5/7/2011 35 PENETRATION ENHANCERS

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5/7/2011 PENETRATION ENHANCERS 37 NEEDLE-FREE JET INJECTORS

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5/7/2011 PENETRATION ENHANCERS 38 Basic principle of phonophoresis . Ultrasound pulses are passed through the probe into the skin fluidizing the lipid bilayers by the formation of bubbles caused by cavitation PHONOPHORESIS

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5/7/2011 PENETRATION ENHANCERS 39 Ultrasound to Enhance Skin Permeability

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5/7/2011 PENETRATION ENHANCERS 40 IONTOPHORESIS Basic principle of iontophoresis. A current passed between the active electrode and the indifferent electrode repelling drug away from the active electrode and into the skin,

ELECTROPORATION:

ELECTROPORATION 5/7/2011 PENETRATION ENHANCERS 41 Skin electroporation (electropermeabilization) creates transient aqueous pores in the lipid by application of high voltage of electrical pulses of approximately 100–1000 V/Cm for short time(milliseconds). These pores provide pathways for drug penetration that travel straight through the horny layer. This technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size including biopharmaceuticals with molecular weights greater that 7kDA..

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5/7/2011 PENETRATION ENHANCERS 42 Basic principle of electroporation . High voltage current is applied to the skin producing hydrophilic pores in the intercellular bilayers via momentary realignment of lipids ELECTROPORATION

MICRONEEDLE:

MICRONEEDLE 5/7/2011 PENETRATION ENHANCERS 43 Basic design of microneedle delivery system devices. Needles with or without hollow centre channels are placed onto the skin surface so that they penetrate the SC and epidermis without reaching the nerve endings present in the upper epidermis.

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5/7/2011 PENETRATION ENHANCERS 44 IN VITRO EVALUATION OF PENETRATION Skin: Rat abdominal , Rabbit, Porcine , Human cadaver Temp.: 32 +/- 1°C . Media: Simulated Fluid. P H : 6.8 FRANZ DIFFUSION CELL

LITERATURE SURVEY ON PENETRATION ENHANCER:

LITERATURE SURVEY ON PENETRATION ENHANCER SR. NO. NAME OF DRUG CPE’s USED INVESTIGATORS JOURNAL 1 5-FU Sesquiterpene (40 fold ) P. A. Cornwell J Pharm Pharmacol 2 Naloxone Lauric acid Bruce J. Aungst J Pharm Pharmacol 3 Acyclovir Azone Mohsen I. Afouna International Journal of Pharmaceutics 4 Caffeine Dimethyl Formamide (12 fold ) Southwell D. Journal of Biomedical Optics 5 Levo norgestrel Alcohols David Friend Journal of Controlled Release 5/7/2011 PENETRATION ENHANCERS 45

REFERENCES :

REFERENCES Remington: The Science & Practice of Pharmacy, 21 st edition, Vol. 2, Lippicott , Williams & Wilkins, 2006,p.n. 959. Jain N.K; Controlled and Novel Drug delivery, CBS Publishers & Distributors, first edition, page no-100. Williams A. C. , Barry B. W. ; Penetration enhancers; Advanced Drug Delivery Reviews ,56, 603– 618(2004) . Heather A.E. Benson; Transdermal Drug Delivery: Penetration Enhancement Techniques; Current Drug Delivery; Bentham Science Publishers Ltd.;, 2, 23-33(2005). Pathan I. B. , Setty C M. ; Chemical Penetration Enhancers for Transdermal Drug Delivery Systems; Tropical Journal of Pharmaceutical Research, 8 ,173-179(2009) . Friend D. , Catz P. , Heller J. , Reid J. , Baker R. , Transdermal delivery of levonorgestrel I. Alkanols as permeation enhancers, J. Control. Release 7 (1988) 243– 250. 5/7/2011 46 PENETRATION ENHANCERS

REFERENCES:

REFERENCES Sinha V. R. , Kaur M. P. ; Permeation Enhancers for Transdermal Drug Delivery; Drug Development and Industrial Pharmacy, 26(11), 1131–1140 (2000). Shembale A. I. , Borole D. K. , Lohiya R. T. ; Useful Permeation Enhancers For Transdermal Drug Delivery: A Review; International Journal of Pharmaceutical Research & Development – Online(IJPRD); 5(2), 1-6(2010). Aungst B.J. , Rogers N.J., Shefter E. , Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides, Int. J. Pharm. 33 225– 234(1986) . Cornwell P.A. , Barry B.W., Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil, J. Pharm. Pharmacol . , 46, 261– 269(1994). Southwell D. , Barry B.W. , Penetration enhancers for human skin: mode of action of 2-pyrrolidone and dimethylformamide on partition and diffusion of model compounds water, n-alcohols and caffeine, J. Invest. Dermatol ., 80, 507– 515(1983) . 5/7/2011 47 PENETRATION ENHANCERS

THANK YOU!:

THANK YOU! 5/7/2011 48 PENETRATION ENHANCERS